Efficacy and safety of transcutaneous auricular vagus nerve stimulation for frequent premature ventricular complexes: rationale and design of the TASC-V trial

Background Premature Ventricular Complexes (PVCs) are very common in clinical practice, with frequent PVCs (more than 30 beats per hour) or polymorphic PVCs significantly increasing the risk of mortality. Previous studies have shown that vagus nerve stimulation improves ventricular arrhythmias. Stimulation of the auricular distribution of the vagus nerve has proven to be a simple, safe, and effective method to activate the vagus nerve. Transcutaneous au ricular vagus nerve stimulation (taVNS) has shown promise in both clinical and experimental setting for PVCs; however, high-quality clinical studies are lacking, resulting in insufficient evidence of efficacy. Methods The study is a prospective, randomized, parallel-controlled trial with a 1:1 ratio between the two groups. Patients will be randomized to either the treatment group (taVNS) or the control group (Sham-taVNS) with a 6-week treatment and a subsequent 12-week follow-up period. The primary outcome is the proportion of patients with a ≥ 50% reduction in the number of PVCs monitored by 24-hour Holter. Secondary outcomes include the proportion of patients with a ≥ 75% reduction in PVCs, as well as the changes in premature ventricular beats, total heartbeats, and supraventricular premature beats recorded by 24-hour Holter. Additional assessments compared score changes in PVCs-related symptoms, as well as the score change of self-rating anxiety scale (SAS), self-rating depression scale (SDS), and 36-item short form health survey (SF-36). Discussion The TASC-V trial will help to reveal the efficacy and safety of taVNS for frequent PVCs, offering new clinical evidence for the clinical practice. Trial registration Clinicaltrials.gov: NCT04415203 (Registration Date: May 30, 2020). Supplementary Information The online version contains supplementary material available at 10.1186/s12906-024-04568-1.


Background
Premature ventricular complexes (PVCs) are the ectopic beats of the ventricular muscle, which are very common even in population without any abnormal structure of the heart.The detection of PVCs is 40-75% through the 24-hour or 48-hour Holter [1,2], and that figure for frequent PVCs is around 7.7% through 24-hour Holter [2].Predictor studies have shown that low education status, smoking, large waist-to-hip ratio, less exercise, taller height, older age, etc. were associated with an increased risk for [3,4].Frequent PVCs are stated as no less than 1 PVCs detected by a 12-lead Electrocardiograph, or more than 30 PVCs per hour [5].More and more studies have revealed that in population with no abnormalities in cardiac structure, frequent PVCs affected the function and structure of left atrial and left ventricular disadvantagely [6], and were associated with the increased risk of cardiovascular risk or death [4,5,7].Patients with frequent PVCs are usually with no symptoms.However, some of them could have desultory fatigue, dizziness, labored breathing and palpitations [8].More serious, continuously developed PVCs can lead to ischemic cardiomyopathy, non-persistent or persistent ventricular tachycardia, and even heart failure [9].β-blockers and non-dihydropyridine calcium channel blockers are still the firstline medicines for PVCs [10].Moreover, the applicable population and side-effects should be noticed.Catheter ablation would be suggested if medication failed.Nonetheless, the application is limited due to its strict indications and high price.Therefore, it is worthwhile to seek a therapy that is effective, well-tolerant, and with few side effects in addition to agents.
Increasing research indicated that there was rich vagal innervation in the ventricle [11], especially in the ventricular myocardium and the ventricular conduction system [12].It has been shown that vagus nerve stimulation can improve ventricular rhythm [13].The auricular branch is the only cutaneous mucocutaneous branch of the vagus nerve, and the stimulation in the ear's distribution area could effectively activate the vagus nerve [14].
Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive and safe physical therapy, which could stabilize the heart rhythm by stimulating the vagus nerve [15].The vagus nervous system belongs to the autonomic nervous system, and the heart is regulated by the autonomic nervous system.Dysregulation of the autonomic nervous system, such as decreased vagal activity and increased sympathetic activity, can lead to arrhythmias and more serious cardiovascular diseases [16].The autonomic nervous system can be regulated by taVNS, which could further enhance the excitability of the vagus nerve, inhibit the activity of the sympathetic nerve, and bring the autonomic nervous system to a balanced state [16].In addition, taVNS has been shown to reduce ventricular interstitial fibrosis, reduce the possibility of ventricular arrhythmias, and stabilize the electrophysiological conduction of cardiomyocytes in models of heart diseases such as myocardial infarction and heart failure [17].The auricular point CO15 (Xin) is in the concha cavity, and HX1 (Erzhong) is in the middle point of the helix, both are in the area of auricular vagus nerve distribution [18].Stimulating on these two points can modulates the excitability of the vagus nerve [19].Besides, laboratory studies have shown that needling in PC6 (Neiguan) and HT7 (Shenmen) stabilizes heart rate by blocking ion channels in tachyarrhythmia cardiomyocytes and stimulating parasympathetic nerves [20][21][22].
Although there was clinical and experimental basis of taVNS for PVCs, but the high-quality clinical studies are limited with insufficient evidence of efficacy.This study preliminarily evaluated the efficacy of taVNS in reducing the number of PVCs in patients with frequent PVCs, and evaluated the acceptability and safety of patients, laying a foundation for further clinical research.

Study design
This is a randomized controlled trial, which is carrying out at three centers in China: Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Peking University Third Hospital Yanqing Hospital and Beijing Longfu Hospital.This trial was started on June 4th, 2020, and will be completed in June 2024 anticipatedly.The flow chart and flow sheet are showed in Fig. 1; Table 1.

Randomization
The random number was generated by a statistician from Clinical Pharmacological Assessment Center of Guang'anmen Hospital by using SAS software through PROC PLAN statement.The random codes were sealed in opaque envelopes and be placed in order according to the serial numbers outside.A staff who was not involved in the treatment and evaluation of this trial keeps these envelopes and is responsible for the assignment.

Blinding
Acupuncturists could not be blinded for that the taVNS is a manipulating intervention.The participants, outcome evaluator and statistician are blinded.Patients will accept taVNS in the treatment group, and sham-taVNS without any current output in the controlled group.For the blinding, patients in both groups were told that the feelings of stimulation they would receive might vary individually, with some could feel it and others could not feel it at all.During the treatment, the sound of adjusting the current was the same in both groups.

Participants
Patients with PVCs will be evaluated for the enrollment.The inclusion criteria contain: (1) diagnosed as the frequent premature ventricular contraction (>720 PVCs through 24 h-Holter) [5] with the Lown grading system of 2, 3 and 4 A [23]; (2) 18 years ≤ age ≤ 75 years; (3) volunteered to participant.Patients will be excluded if they (1) have severe valvular heart disease, congenital heart disease, pericardial disease, hypertrophic cardiomyopathy, unstable angina, acute myocardial infarction, myocarditis, aneurysm, congestive heart failure decompensation period (New York Heart Association classification of III or VI), cardiogenic shock, cerebrovascular disease, hematopoietic system disease, severe mental disease; (2) have bradycardia, including pathologic sinus node syndrome, atrioventricular block no less than the second degree;

Intervention
Two to three acupuncturists from each site with no less than 2 years of acupuncture experience manipulate the taVNS or sham-taVNS.All acupuncturists are the registered practitioners of traditional Chinese medicine.The acupuncturists and outcome evaluators received a systemic training before the recruitment.Both treatments are constitutive of 30 sessions over 6 weeks with 30 min for each session, 5 sessions per week.Huato disposable ear clip electrodes, skin electrodes and Huato SDZ-IIB stimulator will be used (Suzhou Medical Appliance, Suzhou, China).Intervention procedures of the taVNS and sham-taVNS are showed in Figs. 2 and 3.

taVNS group
Participants in taVNS group will receive taVNS and usual care.TaVNS will be performed on HX1(Erzhong) and CO15(Xin).Ear stimulation acupoints are selected according to auricular acupuncture point with the distribution of vagus nerve [18,24].Acupoints of PC6 (Neiguan) and HT7 (Shenmen) will also be stimulated to calm the mind.Ear clip electrodes will be attached to bilateral Erzhong and Xin, skin electrodes will be attached to bilateral PC6 and HT7 with a 10 Hz continuous wave, setting the pulse width of 0.2ms ± 30%.
Usual Care: participants will be encouraged to maintain their routine life if they did not take any medicine; otherwise, they will be allowed to continue their usual medicine treatment for PVCs recommended by the guideline.
The usual care used by the patients was not allowed to alter from the whole study period.

Sham-taVNS group
Participants in Sham-taVNS group will receive Sham-taVNS and usual care.The points, stimulator and stimulating parameters used in Sham-taVNS group are the same with taVNS group.However, we cut the inner electric wire of the stimulator to prevent the current output.Usual Care: the same with the taVNS group.

Outcome
The primary outcome is the proportion of participants with a ≥ 50% decrease of PVCs from baseline at the end of week 6.The PVCs will be assessed by a 24-h Holter.We will calculate the decrease of PVCs between baseline and week 6 (at the end of the treatment) and obtain the proportion of patients with a decrease of 50%.
Secondary outcomes include: (1) the proportion of participants with a ≥ 50% decrease of PVCs from baseline at the end of week 18 and the proportion of participants with a ≥ 75% decrease of PVCs from baseline at the end of week 6 and 18 which will be assessed the same way as the primary outcome; (2) the change from baseline in PVCs, total cardiac impulse and supraventricular premature contractions at the end of week 6 and 18 which will also be assessed through a 24-h Holter; (3) the score change from baseline in the symptom of palpitation, chest tightness, dizziness or insomnia at the end of week 6 and 18; the change of the proportion of participants with moderate/severe symptoms of palpitation, chest tightness, dizziness or insomnia from baseline at the end of week 6 and 18; The symptom of palpitation will be assessed by a 10-scale VAS from 0 to 10, a higher score indicates a more severe symptom; Score 4-6 are defined as the moderate level, Score 7-10 are defined as the severe level; (4) the score change from baseline in the Self Anxiety Scale  SF-36 questionnaire contains eight scales with two measures: physical and mental health.The physical health includes four scales of physical functioning, role-physical, bodily pain, and general health.The mental health is composed of vitality, social functioning, role emotional, and mental health.SF-36 scores from 0 to 100, higher scores indicate better health status.7)subgroup analysis of ages (classified as ≤ 40 years and > 40 years), sex and the severity of PVCs (classified as Grade 2, 3, and 4 A according to Lown grading system) on the primary outcome.8) the proportion of participants with treatmentrelated adverse events between two groups.

Sample size calculation
The null hypothesis is that there would be no difference between the two groups in the proportion of participants with a ≥ 50% reduction of PVCs from baseline after 6 weeks of treatment, and the alternative hypothesis is that there would be a significant difference between the two groups.In our pilot study, the proportion in taVNS and sham-taVNS groups were 58.3% and 21.1%, separately.Ninety participants are required (45 in each group) with a two-tailed test setting power as 90% and alpha as 5%, and considering the rate of loss to follow-up as 15%.To balance the three sites with two groups, 30 participants need to be enrolled in each site (15 per group in one site).

Statistical analysis
All analyses will be performed using the intention-totreat population and a p value of 0.05 will be taken to indicate a statistically significant effect.The primary analysis will seek to demonstrate the ratio difference of participants with a ≥ 50% decrease of PVCs from baseline at the end of week 6 between taVNS and sham taVNS groups.We will use a generalized linear mixed model to estimate the differences from baseline and between groups.
The random effect for participants will be included, the fixed effects include 1 with-subject variable (time point) and 1 between-subject variable (group).Other secondary outcomes with the same pattern of longitudinal data will be analyzed use the similar way as primary analysis.The intervention effect will be summarized as the ratio difference and its 95% confidence interval.For continuous process indicators such as Holter related outcomes and patient reported outcome measures (SAS, SDS, SF-36), we will use mixed effect linear model.A detailed analysis plan including mock tables will be completed before unblinding.For missing data of primary outcome, the multiple imputation method will be used under the missing-at random assumption to generate 100 imputed data sets.All analyses and summaries will be performed by using SAS version 9.4.

Quality control
Prior to the trial, all staff underwent a special training on the purpose and content of the trial, treatment strategies and quality control.Monitors will check case report forms once every week as well as the acupuncture operation during the treatment period.Dropouts and withdrawals including the reasons will be detailed documented through the trial.Participants' information will be stored in locked file cabinets at the study sites with limited access; only investigators have the right to access the data.All investigators will always maintain a strict privacy policy to protect confidentiality before, during and after the trial.

Discussion
In this study, we use taVNS plus usual care, controlled with sham-taVNS plus usual care to initially access the short-term and long-term effect of taVNS for frequent PVCs.Combined with the clinical symptoms of frequent premature ventricular contractions and the reasons that anxiety and depression are closely related to arrhythmia, the PVCs-related symptoms VAS score, SAS score and SDS score are selected as the outcomes in this study aside from the 24-hour Holter, which can improve the report of relevant results.This study would provide clinical practice evidence for the treatment of frequent PVCs, and may help the physicians to make clinical decisions and discover relevant clinical treatments of ventricular arrhythmia.The results of the study will be published after completion of the study.The regulation of the cardiac function is significantly influenced by the vital role played by the vagus nerve.From the anatomical structure, the postganglionic efferent vagus nerve is distributed throughout most of the cardiac system including the atria, the sinoatrial node, the atrioventricular node, the ventricles, et al. [12].Stimulation of the vagus nerve can reduce the cardiac rate, atrioventricular conduction and ventricular contractility [25].Clinical studies have revealed that vagus nerve stimulating can relieve the atrial fibrillation and heart failure by improving the heart rate variability and the left ventricular ejection fraction [26][27][28], which is also supported by animal research [29][30][31].Although not as much as the research on atrial fibrillation and heart failure, there are also some animal studies focusing on the mechanism of vagus nerve stimulation for the ventricular arrhythmia.Vagus nerve stimulation could inhibit the enhancement of sympathetic nerve activity by ventricular muscle [32] and reverse the ventricular arrhythmias induced by high sympathetic nerve stimulation, especially inhibit the ventricular fibrillation and stabilize the ventricular electrophysiological changes [33].However, this protective effect on the ventricle can also be affected by some drugs, such as atropine and β-blockers [34].Besides, the vagus nerve was able to regulate the NO release, which could contract blood vessels, by the ventricular myocytes in order to improve the myocardial systolic and diastolic function, increase coronary blood flow, and improve cardiac function [35].In terms of ventricular electrophysiology, vagus nerve could reduce the maximum slope of the electrocardiogram recovery curve and increase the effective refractory period in the excitatory cycle of ventricular myocytes [36].Due to the risk and complexity of ventricular arrhythmias, there are relatively few clinical studies.For the vagus nerve stimulation for PVCs, especially the taVNS for PVCs, we only searched out a study protocol, which was registered in 2021, later than our registration.
Recent studies have found that as the only branch of the vagus nerve on the body surface, the afferent nerve fibers of the auricular vagus nerve are consistent with the central projection of the cervical vagus nerve [37], and stimulation of the auricular branch of the vagus nerve can also cause the activation of the vagus nervous system.Therefore, taVNS is a safe and effective treatment with high acceptance by patients.In order to implement blinding as successfully as possible, the proper setup of sham taVNs is crucial.Currently, there are mainly two approaches for setting the sham taVNS.One involves applying identical electrical stimulation as the treatment group in areas with no vagus nerve distribution, such as the auricle or the earlobe [38][39][40][41][42]; another entails placing electrodes in the same locations as the treatment group with no electric current [43], which is also adopted in our study.The key point is that before the treatment, participants will be informed that some of the taVNs might be imperceptible, and they may or may not experience any feeling.
Our study has medical limitations.First, due to the small sample size and short follow-up period in this trial, clinical studies with larger sample size and longer follow-up results will be still needed for the evidence support.Second, in terms of blinding, the operator needs to intervene for the patient, so it is impossible to blind the operator.Third, we did not include a waiting-list group; therefore, the natural course of the disease could not be observed.This study will serve as a preliminary evaluation to lay the foundation for further high-quality clinical research.

Conclusion
The TASC-V trial will reveal the efficacy and safety of taVNS for frequent PVCs, and provide new clinical evidence for the clinical practice.
(3) have already had pacemaker or percutaneous coronary intervention, or who plan to have pacemaker or percutaneous coronary intervention; (4) are female during pregnancy or lactation; (5) have sensory loss; (6) are allergic to electric current or transcutaneous patches; (7) blood pressure ≤ 90/60 mmHg; (8) participate in other clinical trials within 3 months before the screening.

(
SAS) at the end of week 6 and 18. SAS contains 20 items scoring from 25 to 100.The higher the score significates the greater anxiety.(5) the score changes from baseline in the Self Depression Scale (SDS) at the end of week 6 and 18. SDS contains 20 items scoring from 25 to 100.The higher the score significates the greater depression.(6) the score changes from baseline in 36-Item Short Form Health Survey (SF-36) at the end of week 6 and 18.The

Table 1
Study schedule by time